Background

Exocrine pancreatic insufficiency (EPI) is a condition characterized by deficiency of the exocrine pancreatic enzymes, resulting in the inability to digest food properly, or maldigestion. The etiology of this deficiency includes both pancreatic and nonpancreatic causes (see Etiology).
[1]

The exocrine pancreas produces 3 main types of enzymes: amylase, protease, and lipase.
[2] Under normal physiologic conditions, the enzymes (specifically, lipase) break undigested triglycerides into fatty acids and monoglycerides, which are then solubilized by bile salts (see Pathophysiology). Because the exocrine pancreas retains a large reserve capacity for enzyme secretion, fat digestion is not clearly impaired until lipase output decreases to below 10% of the normal level.
[3]

The diagnosis of exocrine pancreatic insufficiency (EPI) is largely clinical.
[4] It may go undetected because the signs and symptoms are similar to those of other GI diseases
[5] or because the signs and symptoms are not always evident, due to dietary restrictions (see Presentation and Differential Diagnosis).

A complete laboratory evaluation (including pancreatic function testing) is required not only to diagnose EPI but also to determine the extent of the malabsorption and assess the manifestations of the underlying disease, if present (see Workup).

Management of EPI is based primarily on pancreatic enzyme replacement therapy (PERT) but may also include lifestyle modifications and vitamin supplementation as appropriate (see Treatment).

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Anatomy

The pancreas, named for the Greek words pan (all) and kreas (flesh), is a soft, lobulated, retroperitoneal organ that is 12-15 cm long and roughly J-shaped (like a hockey stick). It lies transversely, though a bit obliquely, on the posterior abdominal wall behind the stomach, across the lumbar (L1-2) spine (see the image below). The pancreas is prismoid in shape and appears triangular in cut section, with superior, inferior, and anterior borders as well as anterosuperior, anteroinferior, and posterior surfaces.

The head of the pancreas lies in the duodenal C loop in front of the inferior vena cava (IVC) and the left renal vein (see the images below). The uncinate process is an extension of the lower (inferior) half of the head toward the left; it is of varying size and is wedged between the superior mesenteric vessels in front (the vein on the right and the artery on the left) and the aorta behind. The pancreatic head constitutes about 50% of the pancreatic parenchymal mass.

The body and tail of the pancreas run obliquely upward to the left in front of the aorta and the left kidney. The pancreatic neck is the arbitrary junction between the head and body of the pancreas. The narrow tip of the tail of the pancreas reaches the splenic hilum in the splenorenal (lienorenal) ligament. The body and tail make up the remaining 50% of the pancreatic parenchymal mass.

The transverse mesocolon (with the middle colic vessels in it) is attached to the anterior surface of the lower (inferior) surface of the body and tail; thus, most of the gland is located in the supracolic compartment. The body and tail of the pancreas lie in the lesser sac (omental bursa) behind the stomach.

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Pathophysiology

The GI tract is responsible for digesting and absorbing food.
[6] Lipids provide the richest source of energy for the body, with 9 calories in every gram of fat; in comparison, carbohydrate and protein contains 4 calories per gram. Whereas protein and carbohydrate begin to undergo digestion in the stomach, triglycerides remain mostly unchanged until they reach the small intestine. Intragastric breakdown accounts for approximately 10% of total lipid digestion.
[6]

The pancreatic enzymes responsible for lipid digestion are inactivated when the pH drops below 5; thus, before digestion can continue in the duodenum, the acidic contents of the stomach must be neutralized. Fortunately, the pancreas also secretes bicarbonate, which increases the pH of the duodenal contents.

The exocrine pancreas produces 3 main types of enzymes: amylase, protease, and lipase.
[2] Under normal physiologic conditions, pancreatic enzymes (specifically, lipase) break the undigested triglycerides into fatty acids and monoglycerides. Bile salts then solubilize these breakdown products to form micelles, which are vehicles for absorbing lipid breakdown products.
[6] Normal fat digestion also depends on postprandial synchrony between delivery of nutrients to the duodenum and discharge of pancreatic enzymes.
[2]

Pancreatic secretion is governed by neural and hormonal mechanisms. The hormones responsible for regulation are secretin and cholecystokinin (CCK). Secretin is secreted in response to acid in the duodenum, causing duct cells to release water and bicarbonate; CCK is secreted in response to protein and fat in the small intestine, stimulating acinar cells to release the pancreatic enzymes (see the image below).

EPI is characterized by a deficiency of these exocrine pancreatic enzymes, which results in inability to digest food properly (ie, maldigestion). Because pancreatic lipase accounts for up to 90% of fat digestion, maldigestion of fat is more profound in EPI than maldigestion of proteins and carbohydrates is.
[6] Because the exocrine pancreas retains a large reserve capacity for enzyme secretion,
[6] fat digestion is not clearly impaired until lipase output decreases to below 10% of the normal level.
[3]

Fat malabsorption precedes malabsorption of other macronutrients.
[7] Bile salt precipitation and subsequent adsorption to undigested food reduces the bile salt pool, and this reduction further impairs fat digestion.
[8] Undigested fat, rather than being absorbed, is excreted in the feces, leading to steatorrhea.

Another factor that contributes to pancreatic steatorrhea is the presence of neurohormonal disturbances, which result in gall bladder hypomotility and accelerated gastric and intestinal transit.
[9] Malabsorption of fat-soluble vitamins A, D, E, and K may accompany EPI.

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Etiology

The etiology of EPI can be classified into pancreatic and nonpancreatic causes.
[10, 11] Pancreatic causes include the following:

Chronic pancreatitis (the most common cause of EPI): This condition has a number of possible causes, but the end result is a metabolic insult to the pancreatic exocrine cells that leads to necrosis, fibrosis and loss of function (see the image below).

Cystic fibrosis: In this condition, reduced chloride transport in the pancreas leads to reduced water content of secretions, precipitation of proteins, and plugging of ductules and acini, preventing the pancreatic enzymes from reaching the gut; autodigestion of the pancreas occasionally leads to pancreatitis.

Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel (see the image below) and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces.

Celiac disease (secondary to decreased pancreatic stimulation): This leads to EPI in about one third of patients and may be an unrecognized cause of treatment failure.

Crohn disease: This is associated with pancreatic autoantibodies that lead to impaired pancreatic exocrine function.

Autoimmune pancreatitis: This is often caused by immunoglobulin G4 (IgG4)-related disease and can progress to EPI.
[13]

Zollinger-Ellison syndrome: This can produce EPI through acid inactivation of pancreatic enzymes; it is corrected by controlling the acid secretion

GI and pancreatic surgical procedures: Any such procedures that lead to loss of postprandial synchrony, decreased pancreatic stimulation, and loss of pancreatic parenchyma can cause EPI.
[14] A study by Huddy et al found that EPI contributes to postoperative morbidity in patients who undergo esophagectomy.
[15] Using multivariate analysis, a study by Dhar et al indicated that in patients with chronic pancreatitis who undergo duodenum-sparing head resection or pancreaticoduodenectomy to relieve abdominal pain, EPI and narcotic requirement are the only predictors of the need for revision surgery.
[16] A study by Okano et al suggested that following pancreatectomy, a remnant pancreatic volume of under 24 mL is the only independent predictor of postoperative EPI. The study included 227 patients.
[17]

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Epidemiology and Prognosis

Because EPI has multiple possible causes and is not usually recorded as a medical statistic, its prevalence and demographics cannot be established with certainty at present. In a German-based study, one of the most common causes of EPI had an age-adjusted prevalence of 8 per 100,000 for males and 2 per 100,000 for women; these numbers are probably relatively close to the prevalence of EPI in most developed countries. No other reliable data are currently available.
[18]

The natural history and progression of EPI depend on the underlying etiology. For example, patients with autoimmune pancreatitis or cystic fibrosis may progress to almost complete insufficiency, whereas those with alcohol-induced EPI may recover from or at least halt the progression of pancreatic insufficiency if they abstain from alcohol. Even with complete loss of exocrine function, however, protease and lipase supplements are effective in restoring normal digestion of dietary nutrients.

Complete replacement of the pancreas with cystic disease and intrahepatic biliary dilation caused by extrinsic compression of the common bile duct. Note also the renal cysts and masses. This patient had exocrine pancreatic insufficiency. Image courtesy of Wikimedia Commons.